Dibenzo(c,e)azepin-5-ones

ABSTRACT

Novel substituted-dibenzo(c,e)azepin-5-ones. The dibenzo(c, e)azepin-5-ones disclosed herein are potent anti-inflammatory, anti-pyretic and analgesic agents. Also included herein are pharmaceutical compositions containing said dibenzo(c,e)azepin-5one compounds as an active ingredient, and methods of treating inflammation, fever and pain in patients by administering said compounds. Further encompassed is 6,7-dihydro-5H-dibenzo(c, e)azepin-5-one possessing novel anti-inflammatory, anti-pyretic and analgesic activities.

United States Patent [191 Pessolano et al.

[ 11 3,821,201 June 28, 1974 DIBENZO(C,E)AZEPIN-5-ONES [73] Assignee: Merck & Co., Inc., Rahway, NJ.

[22] Filed: Aug. 9, 1971 [21] Appl. No.: 170,384

[52] U.S. Cl. 260/239.3 T, 424/244 [51] Int. Cl C07d 41/08 [58] Field of Search 260/2393 T [56] 0 References Cited UNITED STATES PATENTS 3,551,414 12/1970 Hawthorne et al 260/2393 T Primary EXaminer I-Ienry R. Jiles Assistant ExaminerRobert J. Bond Attorney, Agent, or Firm-Harry E. Westlake, Jr.; Julian S. Levitt; William l-LNicholson [5 7] ABSTRACT Novel substituted-dibenzo[c,e]azepin-5-ones. The dibenzo[c,e]azepin-5-ones disclosed herein are potent anti-inflammatory, anti-pyretic and analgesic agents. Also included herein are pharmaceutical compositions containing said dibenzo[c,e]azepin-5-one compounds as an active ingredient, and methods of treating inflammation, fever and pain in patients by administering said compounds. Further encompassed is 6,7- dihydro-S H-dibenzo[c,e ]azepin-5-one possessing novel anti-inflammatory, anti-pyretic and analgesic activities.

13 Claims, N0 Drawings 1 DIBENZO(C,E)AZEPIN-5-ONES This invention relates to novel substituted-dibenzo [c,e]azepin-5-ones and methods for preparing the same. Also included within the scope of the invention are pharmaceutical compositions containing said dibenzo[c,e]-azepin-5-one compounds as active ingredients. The novel dibenzo[c,e]azepin-5-ones of the invention are potent anti-inflammatory, anti-pyretic and analgesic agents which are effective in the method of counteracting inflammation, pain and fever.

In the past, numerous compounds have been widely used in the treatment of inflammation, pain and fever. The compounds employed in said treatment have consisted of both steroids and non-steroids. These compounds have shown side effects ranging from a simple headache to psychic and gastrointestinal disturbances.

In a continuous search for potent anti-inflammatory, anti-pyretic and analgesic agents, we have found a class of novel dibenzo[-c,e]azepin-5-ones which are highly effective in the treatment of inflammation, pain and fever. The novel dibenzo[c,e]azepin-5-ones are of value in the treatment of arthritic and dermatological disorders of like conditions responsive to anti-inflammatory drugs. In general they are indicated for a wide variety of conditions where one or more of the symptoms of inflammation, fever and pain are manifested. Included within this category are diseases such as rheumatoid arthritis, osteo-arthritis, gout, infectious arthritis and wherein n, R2, R and R are eac hydrogen, halogen, such as fluorine,

bromine and the like, alkoxy, such as methoxy,

ethoxy,

isopropyloxy,

butoxy and the like, nitrile, hydroxy,

nitro, amino, alkyl, such as methyl p py ethyl, t-butyl and the like, dialkylamino, such as dimethylamino, diethylamino, methylethylamino and the like, dialkenylamino, such as I dibutenylamino, dipentenylamino, dipropenylamino and the like, alkylamino, such as methylamino, ethylamino, butylamino and the like, arylamino, such as anilino, o,m or p-tolylamino, anisidino and the like, aralkylamino, such as benzylamino, phenethylamino, o,m or p-methoxybenzylamino, o,m or p-halobenzylamino, alkenylamino, such as butenylamino, propenylamino and the like, aroyl, such as benzoyl, o,m or p-halobenzoyl, o,m or p-methylthiobenzoyl, aroylamino, such as benzoylamino, o,m or p-halobenzoylamino, o,m or p-methoxybenzoylamino, o,m or p-methylthiobenzoylamino, acylamino, such as acetylamino, propionylamino, butyrylamino and the like, acyl, such as acetyl, propionyl, butyryl and the like, mercapto, alkylthio, such as methylthio, ethylthio, butylthio and the like, arylthio, such as phenylthio, o,m or p-tolylthio and the like, aralkylthio, such as benzylthio, o,m or p-methylbenzylthio, o,m or p-methoxybenzylthio, phenethylthio and the like, alkenylthio, such as butenylthio, propenylthio and the like, alkylsulfoxide, such as methylsulfoxide, ethylsulfoxide,

propylsulfoxide and the like, alkenylsulfoxide, such as allylsulfoxide and the like, arylsulfoxide, such as phenylsulfoxide,

o,m or p-tolylsulfoxide and the like, aralkylsulfoxide, such as benzylsulfoxide,

phenethylsulfoxide and the like, alkylsulfone, such as methylsulfone,

ethylsulfone,

isopropylsulfone,

butylsulfone and the like, alkenylsulfone, such as butenylsulfone,

propenylsulfone and the like, arylsulfone, such as phenylsulfone,

o,m or p-tolylsulfone'and the like, aralkylsulfone, such as benzylsulfone,

phenethylsulfone,

o,m or p-methylbenzylsulfone and the like, carbamoyl, monoor dialkylcarbamoyl, such as methylcarbamoyl,

dimethylcarbamoyl,

diethylcarbamoyl,

butylcarbamoyl and the like, arylcarbamoyl, such as phenylcarbamoyl,

anisidinocarbamoyl, and the like, aralkylcarbamoyl, such as benzylcarbamoyl,

o,m or p-methylbenzylcarbamoyl phenethylcarbamoyl and the like, monoor dialkenylcarbamoyl, such as propenylcarbamoyl,

butenylcarbamoyl,

pentenylcarbamoyl,

dipropenylcarbamoyl and the like, amidino, ureido, carbamoyloxy N-alkylcarbamoyloxy, such as N-methylcarbamoyloxy N-ethylcarbamyloxy N-isopropylc'arbamyloxy N-butylcarbamyloxy and the like, N-dialkylcarbamoyloxy, such as N-dimethylcarbamoyloxy,

N-diethylcarbamoyloxy N-dibutylcarbamoyloxy and the like, haloalkyl, such as difluoromethyl,

fluoromethyl,

trifluoromethyl,

trichloromethyl, bromomethyl, chloromethyl, tribromoethyl and the like,

sulfamyl,

alkylsulfamyl, such as methylsulfamyl, ethylsulfamyl, isopropylsulfamyl,

butylsulfamyl and the like, dialkylsulfamyl, such as dimethylsulfamyl, diethylsulfamyl, methylethylsulfamyl, di-isopropylsulfamyl and the like, haloalkoxy, such as trifluoromethoxy, difluoromethoxy, dibromoethoxy, dichloromethoxy, trifluoroethoxy, fluoromethoxy and the like, haloalkylthio, such as trifluoromethylthio, difluoromethylthio, fluoromethylthio, bromomethylthio, dichloroethylthio, trifluoroethylthio and the like, alkenyloxy, such as propenyloxy, ethenyloxy and the like, aryloxy, such as phenoxy, o,m or p-halophenoxy, o,m or p-tolyloxy, o,m or p-methoxyphenoxy and the like, aralkyloxy, such as benzyloxy, phenethyloxy, o,m or p-methoxybenzyloxy, o,m or p-methylbenzyloxy and the like, carboxyalkyl, such as carboxymethyl,

a-carboxyethyl and the like, carboxyalkenyl, such as a-c arboxy( ethylidenyl a-carboxy(butenyl) and the like; R is hydrogen, alkyl, such as methyl, ethyl, propyl and the like, acyl, such as acetyl, propionyl, butyryl and the like, aroyl, such as o,m or p-halobenzoyl, benzoyl and the like, alkoxyalkyl, such as nethoxymethyl, methoxyethyl, propyloxymethyl and the like, aminoalkyl, such as aminoethyl, aminopropyl, aminobutyl and the, like, carboxyalkyl, such as carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl and the like, hydroxyalkyl, such as hydroxymethyl, hydroxyethyl,

hydroxybutyl and the like, alkenyl, such as propenyl, v butenyl and the like; and alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, isopropyloxycarbonyl and the like, carbamoyl, carboxyalkoxy, such as carboxymethoxy, carboxyethoxy, carboxyis'opropyloxy and the like, mercaptoalkyl, such as mercaptomethyl, mercaptoethyl, I mercaptoisopropyl, mercaptobutyl and the like, 'alkylthioalkyl, such as methylthiomethyl, methylthiomethyl, methylthioethyl, ethylthiomethyl, ethylthioethyl, isopropylthioethyl and the like, aralkylthioalkyl, such as benzylthioethyl, o,m or p-methylbenzylthioethyl, o,m or p-methoxybenzylthiomethyl, phenethylthioethyl, benzylthiomethyl and the like, aralkylsulfinylalkyl, such as benzylsulfinylethyl, phenethylsulfinylethyl, o,m or p-methylbenzylsulfinylmethyl, o,m or p-methoxybenzylsulfinylethyl, o,m or p-halobenzylsulfinylethyl, v o,m or p-aminobenzylthioethyl and the like;

R is hydrogen, acylimido, or acetylimido; with the proviso that when R is hydrogen or alkyl at least one of R R and R is other than hydrogen.

This invention may be better understood from the details shown below.

The novel compounds of the invention are prepared by employing 6,7-dihydro-5H-dibenzo[c,e]azepin- 5-one (A) as the starting material wherein R is hydrogen. To obtain the compounds of the invention wherein R is hydrogen, said starting material (A) is treated with a nitrating reagent whereby there is obtained a mono-nitro derivative in the ring containing position 8,9,10 and ll (B) or a dinitro derivative where the other ring containing position 1,2,3 and 4 is nitrated (L). The nitro substituent of the compound thus obtained is reduced to obtain monoor di-amino-6,7- dihydro-5Hdibenzo[c,elazepin-S-one (C). This amino compound is then diazotized and converted to the corresponding monoor di-haloazepin-S-one (D). Treating the compound thus obtained with a cyano forming reagent yields the corresponding monoor di-cyanoazepin-S-one (E). This compound is then hydrolyzed to obtain the corresponding monoor di-carbamoylazepin-S-one (F). Said carbamoyl compound is further hydrolyzed to obtain the corresponding acid (G). This compound is then treated with a trihalo forming reagent to yield the corresponding monoor ditrihalomethyl compound (V). Said monoor di-trihalo compound (V) is then treated with an R forming reagent thereby obtaining the corresponding N-substituted compound (W). The carboxy compound (G) is then treated with an acid halide forming reagent to obtain the corresponding monoor di-acid halide (H). Reacting this compound with an amino reagent gives the corresponding monoor di-substituted-carbamoyl (I). Said Monoor di-substituted carbamoyl compound (I) is then treated with an R forming reagent whereby there is obtained the corresponding N-substituted compound (J). Also, compound (E) is treated with an alkoxyamidino forming reagent to obtain the corresponding monoor di-(alkoxyamidino)azepin 5-one (Q). Said monoor di-(alkoxyamidino) compound (0') is then converted to the corresponding monoor di-(amidino)- 6,7-dihydro-azepin-5-one (R).

The novel monoor di-substituted-6,7-dihydro-N- substituted-SH-dibenzo[c,e]azepin- 5-ones are obtained as shown below. 6,7-Dihydro-5l-l-dibenzo[c- ,e]azepin-5-one (A) is treated with an R forming reagent whereby there is obtained N-R -6,7-dihydro-5l-ldibenzo[c,e]azepin-5-one (R). Monoor di-nitro-6,7- dihydro-SH-dibenzo[c,e]azepin-5-one (B) is treated with an R reagent to obtain monoor dinitro-N-R -,-6,7- dihydro-5l-l-dibenzo[c,e]azepin-5-one. (S). Compound (S) is then reduced to obtain the corresponding monoor di-amino-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one (Y). The compound (Y) thus obtained is then treated with a diazotizing reagent in the presence of an acid to obtain the corresponding monoor di-hydroxy-dibenzo[c,e]azepin-S-one (B'). Treating said monodi hydroxy compound (B') with an alkyl halide or aralkyl halide yields the corresponding monoor di-(alkoxy or aralkoxy)-6,7-dihydro-dibenzo[c,e]azepin-5-one (A). Compound (A) is then nitrated to obtain the corresponding nitro-, monoor di-(alkoxy or aralkoxy)- azepin-S-one (J compound (B') is treated with an alkylcarbamyloxy forming reagent whereby there is obtained the corresponding monoor di-alkyl-carbamyloxy-azepin-S-one (L). Also, said compound (B') can be treated with a haloalkoxy forming reagent to obtain the corresponding monoor di-(haloalkoxy)- azepin-S-one (K). Treating compound (Y), N-substituted-monoor di-amino-6,7-dihydro-5H-dibenzo[c- ,e]-azepin-5-one with a mercapto forming reagent gives the corresponding mono-or di-mercapto-azepin-5-one (M'). SAid mono or di-mercapto compound (M') is then converted to the corresponding monoor di- (haloethylthio)-azepin-5-one (0'). Also, compound (Y) is treated with a ureido forming reagent to obtain the corresponding monoor di-(ureido)-6,7-dihydroazepin-S-one N Compound (C), monoor di-amino-6,7- dihydrodibenzo[c,e]azepin-5-one, is treated with an acyl, aroyl or aralkyloyl forming reagent whereby there is obtained the corresponding monoor di-acyl, aroyl or aralkyloyl-6-acetyl, aroyl or aralkylOyl-azepin-S-one (T). Said compound (T) is then nitrated to obtain the corresponding nitro-monoor di-(acetylamino, aroylamino or aralkoyl-amino)-6,7-dihydro-azepin- 5-one (P' Also, compound (C) is treated with a diazotizing reagent in the presence of an acid to obtain monoor di-hydroxy- 6,7-dihydro-dibenzo[c,e]azepin 5-one (M).

The novel monoor di-sulfur derivatives of the invention are obtained by employing compound (D), monoor di-halo-6,7-dihydro-dibenzo[c,e]azepin-5-one as the starting material. Compound (D) is treated with an R forming substituent to obtain the corresponding monoor di-halo-N-substituted-azepin-S-one (N). Compound (N) is treated with an alkyl, aryl or alkyl-sulfide forming reagent to yield the corresponding monoor dialkyl, aryl or aralkylthio-azepin-S-one (U). lf desired, the monoor di-alkyl, aryl or aralkylthio substituent may be converted to the mercapto substituent. The compound (U) thus obtained is then treated with an oxidizing reagent to yield the corresponding monoor di-alkyl, aryl or aralkyl-sulfinyl-azepin-S-one (X). Further oxidation of this sulfinyl compound gives the corresponding monoor di-alkyl, aryl or aralkylsulfoneazepin-S-one (C').

To obtain the novel compounds of the invention wherein R is other than hydrogen, 6,7-dihydro-5H- dibenzo[c,e]azepin-5-one (A) or monoor di-nitro-N- substituted-6.7-dihydro-dibenzo[c,e]azepin-5-one (S) is employed as the starting material. Said starting material (A or S) is treated with an N-halo-imide to yield the corresponding 7-imido-azepin-5-one compound (K or Z). v

To obtain the novel monoor di-(cyano, carbamoyl or carboxy)-N-R -6,7-'dihydro-diben2o[c,e]azepin- 5-one compounds of the invention wherein R is as previously defined, monoor di-cyano-6,7-dihydro-dibenz0[c,e]azepin-5-one (E) is employed as the starting material. Said starting material (E) is treated with an R forming substituent whereby there is obtained monoor di-cyano-N-R -6,7-dihydro-dibenzo[c,e]azepin- 3O 8 5-one (O) This compound is then hydrolyzed to obtain the corresponding monoor dicarbamoyl-azepin-S-one (P). Said carbamoyl compound (P) is further hydroylzed to yield the corresponding monoor di-carboxyazepin-S-one (Q).

Compound (A), 6,7-dihydro-5H-dibenzo[c,e]azepin-S-one, is treated with an alkoxycarbonyl forming reagent whereby there is obtained the corresponding 6-alkoxycarbonyl-azepin-5-one (E). This compound is then converted to the corresponding 6-aminocarbonylazepin-S-one (D'). Also, compound (A) is treated with an alkylthioalkyl forming reagent to obtain 6- (methylthiomethyl)-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one (F The compound thus obtained is then oxidized to yield the corresponding 6- (methylsulfinylmethyl)-6,7-dihydro-azepin-S-one (G The novel monoordi-sulfamyl derivatives of the invention are obtained by employing compound (R) as the starting material, wherein R is as previously defined. Said starting material (R), N-substituted-6,7- dihydro-5H-dibenzo[c,e]azepin-5-one is treated with a sulfamyl forming reagent whereby there can be obtained the corresponding N substitute'dmonoor disulfonyl halide-azepin-5-one (H) intermediate, and the corresponding N-substituted-mono-or di-sulfamylazepin-5-one (l). y

Flow Sheet 1 represents the general sequence for the preparation of the novel compounds of the invention (c Y, L,

like; and aralkyl suchas benzyl, phenethyl, 0, m or pmethylbenzyl, o, m or p-methoxybenzyl and the like; 55

R is alkyl such as methyl, ethyl, isopropyl and the like; Y is halogen such as fluorine, bromine and the like; X is an integer ranging from 1 4; and N is an integer equal to 0 to 1.

16 g r: e Q \& o= o u 7 t? 1 s \4 h i Q 0:5 a r "g 9 I f v 3: l 1; o P \J q 1") REACTIONS AND CONDITIONS Step 1.1

bination of sulfuric acid and potassium nitrate at room temperature until the reaction is complete. Step 1.2

The reaction is performed by hydrogenation over a catalyst such as palladium-on-carbon, platinum, Raney nickel, and the like, in the presence of an inert solvent such as ethanol, propanol, butanol, benzene, toluene, tetrahydrofuran, ether and the like, at temperatures ranging from C. to near reflux. Of particular preference is the combination of palladiuni-on-carbon and ethanol at room temperature until the reaction is complete.

Step 1.3

The reaction is performed in a water-acid solvent such as water-sulfuric acid, water-fluoroboric acid, water-hydrochloric acid, water-p-toluenesulfonic acid and the like, in the presence of a diazotizing agent such as sodium nitrite, nitrous acid and the like, with a halogenating reagent such as cuprous halide (cuprous chloride, cuprous bromide, cuprous fluoride and the like), at temperatures ranging from 0C. to reflux. Of particular preference is the combination of water-fluoroboric acid and sodium nitrite at 90C. until the reaction is complete.

Step 1.4

The reaction is performed in an inert solvent such as dimethyl formamide, benzene, toluene, ethanol, dimethylsulfoxide, dimethoxyethane, and the like, with a cyano forming reagent such as cuprous cyanide, alkali cyanide (potassium, lithium and the like), at temperatures ranging from room temperature to reflux. Of particular preference is the combination of dimethylformamide and cuprous cyanide at reflux until the reaction is complete.

Step 1.5

The reaction is performed in an acid such as sulfuric, phosphoric, methanesulfonic and the like, at temperatures ranging from 0C. to 50C. Of particular preference is sulfuric acid at room temperature until the reaction is complete.

Step 1.6

The reaction is performed in an inert solvent such as chloroform, benzene, toluene, dimethylsulfoxide, ether and the like, with a N-halo-acylimide such as N- bromosuccinimide, N-chlorosuccinimide, and the like, at temperatures ranging from near reflux to reflux. Of particular preference is the combination of chloroform and N-bromosuccinimide at reflux until the reaction is complete.

Step 1.7

. The reaction is performed in an inert solvent such as ether, dimethylsulfoxide, tetrahydrofuran, benzene, toluene and the like, in the presence of a base such as sodium hydride, sodium amide, potassium hydroxide and the like with an alkyl halide such as methyl iodide, propyl bromide, butyl iodide and the like, or an alkenyl halide such as allyl bromide, vinyl iodide, propenyl chloride and the like, at temperatures ranging from 0C. to 60C. Of particular preference is the combination of dimethylformamide, sodium hydride and allyl bromide at room temperature until the reaction is complete.

Steps 1.9 and 1.13

The reaction is performed with an acyl, aroyl or aralkoyl forming reagent such as acetic anhydride, propionic anhydride, benzoic anhydride, benzoyl chloride, phenyl propionyl chloride and the like, at temperatures ranging from 60C. to near reflux. Of particular preference is acetic anhydride at 90C.-95C. until the reaction is complete.

Step 1.11

The reaction is performed by diazotizing the amine in an aqueous acid solution such as sulfuric acid, hydrochloric acid, and the like, with sodium nitrite, and raising the temperature from 0C. to 100C. until the reaction is complete. Step 1.12

The reaction is performed in an inert solvent such as dimethylformamide, benzene, tetrahydrofuran, ether, toluene, and the like, in the presence of a base such as sodium methoxide, ammonium hydroxide, potassium hydroxide and the like, with alkyl halide, aryl halide or aralkyl halide such as methyl iodide, propyl iodide,

benzyl iodide and phenethyl chloride at temperatures ranging from 0C. to 50C. Of particular preference is the combination of dimethylformamide, sodium methoxide and methyl iodide at room temperature until the reaction is complete. Step 1.14

The reaction is performed with copper, lutidine and dialkyldisulfide such as dimethyldisulfide, diethyldisulfide, diphenyldisulfide, benzyldisulfide and the likecomplex at temperatures ranging from C. to 175C. Of particular preference is dimethyldisulfide complex at 155C. until the reaction is complete. Step 1.15

The reaction is performed in a combination of inert v solvents such as acetone-methanol, water-acetone, methanol-water, benzene-ethanol and the like, with an oxidizing agent such as sodium periodate, oxygen, hydrogen peroxide and the like, at temperatures ranging from 20C. to 50C. Of particular preference is the combination of acetone-methanol and sodium periodate at room temperature until the reaction is complete.

Step 1.16

The reaction is performed in an acid such as acetic acid, propionic acid, N-butyric acid and the like, with an oxidizing agent such as hydrogen peroxide, sodium periodate, oxygen and the like, in the presence of the acid employed as the solvent, at temperatures ranging from 0C. to 60C. Of particular preference is the combination of acetic acid and hydrogen peroxide-acetic acid at room temperature until the reaction is complete.

Step 1.17

The reaction is performed with an acid such as sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, methanesulfonic acid and the like, in the presence of a diazotizing reagent such as sodium nitrite, nitrous acid and the like, at temperatures ranging from 40C. to C. Of particular preference is the combination of sulfuric acid and sodium nitrite at 75C. until the reaction is complete. Step 1.18

The reaction is performed with or without an inert solvent such as ether, benzene, and the like, and an acid halide forming reagent such as phosphorus trichloride, phosphorus pentachloride, thionyl chloride, phosphorus tribromide and the like, at temperatures ranging from room' temperature to reflux. Of particular preference is thionyl chloride at reflux until the reaction is complete. Step 1.19

The reaction is performed with an aqueous monoor di-alkylamine such as methylamine, dimethylamine, propylamine; monoor di-arylamine or monoor diaralkylamine such as aniline, diphenylamine, benzylamine, dibenzylamine, B-phenethylamine and the like,

at temperatures ranging from 10C. to 60C. Of particular preference is dimethylamine at room temperature until the reaction is complete. Step 1.20

The reaction is performed in the presence of a hydrohalic acid such as hydrochloric acid, hydrobromic acid, hydrofluoric acid and the like, with a halogenating reagent such as sulfur tetrafluoride, sulfur tetrachloride, sulfur tetrabromide and the like, in a stainless steel container at temperatures ranging from 50C. to 175C. Of particular preference is the combination of hydrofluoric acid and sulfur tetrafluoride at 120C. until the reaction is complete; Step 1.21

The reaction is performed in an inert solvent such as dimethylforrnamide, tetrahydrofuran, dioxane and the like, with an alkyl halocarbonate such as ethyl chlorocarbonate, methyl chlorocarbonate and the like, at temperatures ranging from C. to room temperature. Of particular preference is the combination of dimethylforrnamide and ethyl chlorocarbonate at C. until the reaction is complete. Step 1.22

The reaction is performed in a base such as ammonium hydroxide, methylamine, methylethylamine, dimethylamine, and the like, at temperatures ranging from 10C. to 50C. Of particular preference is ammonium hydroxide at 35C. until the reaction is complete.

Step 1.23

The reaction is performed in an inert solvent such as dimethylfonnamide, tetrahydrofuran, dioxane, benzene and the like, in thepresence of a base such as NaH, LiH and the like, with a haloalkyl alkyl sulfide such as chloromethyl methyl sulfide, chloroethyl ethyl sulfide and the like, at temperatures ranging from 0C. to room temperature. Of particular preference is the combination of dimethylforrnamide'and chloromethyl methyl sulfide at 10C. until the reaction is complete.

Step 1.24

The reaction is performed in a solvent such as ace-' tone, acetic acid, dimethylforrnamide and the like, with an oxidizing agent such as sodium periodate, potassium periodate and the like at temperatures ranging from 10C. to 40C. Of particuar preference is the combination of sodium periodate and acetone at room temperature until the reaction is complete.

Steps 1.25 and 1.26 v

The reaction is performed in a halosulfonic acid such as chlorosulfonic acid. This intermediate is added to a base such as ammonium hydroxide, methylamine, dimethylamine and the like, attemperatures below 30C. until the reaction is complete.

Steps 1.27 and 1.31

The reaction is performed in an inert solvent such as dimethylforrnamide, tetrahydrofuran, dioxane and the like, with a haloalkene at temperatures ranging from 60C. to 120C. in a sealed container. Of particular preference is the combination of dimethylforrnamide and fluoro-chloro ethylene at 100C. until the reaction is complete.

Step 1.28

. The reaction is performed in an inert solvent such as tetrahydrofuran, methylene chloride, dioxane, dimeth ylformamide and the like, with an alkyl isocyanate such as ethyl isocyanate, methyl isocyanate and the like, at temperatures ranging from 10C. to C Of particular preference is the combination of dioxane and ethyl isocyanate at room temperature until the reaction is complete. I

Step 1.29

The reaction is performed in an acid such as acetic, propionic, hydrochloric and the like, with an alkali isocyanate such as potassium isocyanate, sodium isocyanate and the like at temperatures ranging between 10C and 40C. Of particular preference is the combination of acetic acid and potassium isocyanate at room temperature until the reaction is complete.

Step 1.30

The reaction is performed with a diazotizing agent, treated with an alkali alkyl xanthate such as potassium xanthate, sodium xanthate and the like, and hydrolyzed.

Step 1.32 and 1.33

The reaction is performed in an alkanol solvent such as methanol, ethanol, propanol and the like and a reagent such as hydrochloride, hydrobromide and the like. This intermediate is added to a base such as ammonia, methylamine, dimethylamine and the like, at temperatures ranging between 0C. and room temperature. Of particular preference is the combination of ethanol, hydrochloride and ammonia at 0C. until the reaction is complete.

Representative compounds of the invention are:

9-fluoro-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one 3,9-difluoro-6,7-dihydro-5H-dibenzo[c,e]azepin- S-one 3,9-dinitro-6,7-dihydro-5H-dibenzo[c,e]azepin- 5-one 6,7-dihydro-5H-dibenzo[c,e]azepin-5-one 6-acetyl-6,7-dihydro-5H-dibenzo[c,elazepin-S-one 9-chloro-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one 6-butyryl-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one 9-nitro-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one 6-allyl-6,7-dihydro-5l-l-dibenzo[c,e]azepin-5-one 9-amino-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one 9-hydroxy-6,7-dihydro-5H-dibenzo[c,e]azepin- S-one 6-hydroxymethyl-9-dimethylamino-6,7-dihydro-5H- dibenzo[c,e]azepin-S-one 9-cyano-6,7-dihydro-5l-l-dibenzo[c,e]azepin-5one 9-methoxy-6,7-dihydro-5l-l-dibenzo[c,e]azepin- 5-one 9-carbamoyl-6,7-dihydro-5H-dibenzo[c,e]azepin- 5-one 9-trifluoromethyl-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one 9-N,N-dimethylcarbamoyl-6,7-dihydro-5l-l-dibenzo[c,e]azepin-5-one 9-carboxy-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one 9-methylmercapto-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one 6-methyl-6,7-dihydro-5 H-dibenzo[c,e]azepin'-5-one 6-acetyl-9-acety1amino-6,7-dihydro-5 H-dibenzo[c- ,e]azepin-S-one 6-methyl-9-nitro,6,7-dihydro-5H-dibenzo c ,e azepin-S-one 6-allyl-9-trifluoromethyl-6,7-dihydro-5H-dibenzo[c- ,e]-azepin-5-one 6-propionyl-3,9-di(dimethylamino)-6,7-dihydro-5 H- dibenzo-[c,e]azepin-5-one 6-propionyl-9-fluoro-6,7-dihydro-5H-dibenzo[c- ,e]azepin-5-one- 3-fluoro-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one 21 6-acetyl-3,9-dichloro-6,7dihydro-5H-dibenzo[c- ,c lazepin-S-one 3,9-difluoro-o-acetyl-o,7-dihydro-H-dibenzo[c- ,elazepin-S-one 6-acetyl-3,9-diacetylamino-6,7-dihydro-5H- dibenzo[c,e]azepin-5-one 6-butyryl-9-fluoro-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one 6-hydroxymethyl-9cyano-6,7-dihydro-5H- dibenzo[c,e]azepin-5-one 7-succinimido-6,7-dihydro-5H-dibenzo[c,e]azepin- 5-one 6-butyryl-9-hydroxy-6,7-dihydro-5H-dibenzo[c- ,elazepin-S-one 6-benzoyl-3,9-dinitro-6,7-dihydro-5H-dibenzo[c- ,e]azepin-'5-one 6-allyl-3,9-dinitro-6,7-dihydro-5H-dibenzo[c,e]azepin-S-one The compounds of this invention are administered 0- rally, topically, intravenously, or intramuscularly in thetreatment of inflammation, fever and pain. Of particular preference is the oral form ranging from 10 to 2,000 mg./kg. of body weight per day. Of preference is 50-500 mg./kg. of body weight per day for varying periods of treatment as required. Comparable amounts of the compounds may be administered in topical or parenteral forms.

For these purposes the compounds of the invention may be administered orally, topically and parenterally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes intravenous or intramuscular. In addition to the treatment of warm-blooded animals such as mice, rats, horses, dogs, cats, etc., the compounds of the invention are effective in the treatment of humans.

The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide a pharmaceutically elegant and palatable prepareation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for manufacture of tablets. These excipients may be, for example, inert dilu ents such as calcium carbonate, sodium carbonate, lac-' tose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, maize starch or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastro-intestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material-such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example arachis oil, peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example, polyoxyethylene sorbitan monooleate. The said aqueous suspensions may also contain one or more preservatives, for example, ethyl or npropyl p-hydroxy benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example, arachis oil, olive oil, sesame oil, or coconutoil, or in a mineral oil such as liquid paraffin' The oil suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the additionof water provide the active ingredient in admixture with v a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring and coloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example, olive oil or arachis oils, or a mineral 01, for example, liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example, gum acacia or gum tragacanth, naturally-occurring phosphatides, for example, soya bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan mono-oleate, and condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for example, glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.

For intravenous and intramuscular administrations, the pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in a 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringers solution, and isotonic sodium chloride solution. ln addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic monoor di-glycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The amount of active ingredient that may be com- I bined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration of humans may contain from 5 mg. to 10 grams of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Dosage unit forms will generally contain between from about 175 mg. to about 1.75 g. of active ingredient. Comparable amounts of the compounds may be administered in topical or parenteral forms.

It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

The starting material employed in the invention is represented by compound (A) which is shown in Flow Sheet I. Said starting material is known and processes for its preparation can be found in the literature. For example, see U.S.S.R. Patent 261,390 and US. Pat. No. 3,551,414.

The following examples illustrate the preparation of the various 6,7-dibenzo[c,e]azepin-5-one compounds described herein as anti-inflammatory, anti-pyretic and analgesic agents. The examples should be construed as illustrations of the invention rather than limitations thereof.

EXAMPLE 1 9-Nitro-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one A solution of 4.2 g. (.02 mole) of 6,7-dihydro- 5H-dibenzo[c,elazepin-S-one in 60 ml. of concentrated sulfuric acid is cooled to C. and to it is added, with stirring, a solution containing 2 g. of potassium nitrate in 20 ml. of sulfuric acid over a period of 1 hour at a temperature below 5C. The reaction is then stirred for 5 hours at room temperature, poured onto ice, filtered and washed with water and sodium bicarbonate solutions. The crude product, 9-nitro-6,7-dihydro-5H- dibenzo[c,elazepin-S-one, is recrystallized from dimethylformamide, mp. 250-252C.

EXAMPLE 2 9-Amino-6,7-Dihydro-5H-dibenzo[c,e]azepin-5-one Five grams of 9-nitro -6,7-dihydro-5H-dibenzo- [c,e-

lazepin-S-one in 150 ml. of ethanol is hydrogenated in the presence of 1 g. of 5% palladium-on-charcoal. The

catalyst is removed by filtration, the solvent concentrated in vacuo and the residue is extracted with dilute hydrochloric acid. The acid extracts are neutralized with ammonium hydroxide to yield the crude product, 9-amino-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one. This product is recrystallized from dimethylformamid by the addition of ether, mp 275279C. When 9-nitro-6-acetyl, benzoyl, or methyl-6,7- dihydro-5H-dibenzo[c,e]azepin-5-one is substituted for 9-nitro-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one, there is obtained 9-amino-6-acetyl, benzoyl, or methyl- 6,7-dihydro-5H-dibenzo[c,e]azepin-5-one.

EXAMPLE 3 9-Fluoro-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one To 1.1 g. (.005 mole) of 9-amino-6,7-dihydro-5H- dibenzo[c,e]azepin-5-one in 3.5 ml. of 48% fluoboric acid at 0C is added a solution containing 415 mg. of sodium nitrite and 2 ml. of water over 10 minutes. The reaction mixture is maintained at 0C. for 20 minutes, then cooled with dry ice-acetone to precipitate a solid. The solid is suspended in ml. of heptane and heated on the steam-bath for 3 hours at C., cooled and decanted from a tacky solid which is extracted with 30 ml. of warm methylene chloride. The extract is diluted with petroleum ether to crystallize the boron trifluoride complex of the 9-fluoro product. This is decomposed by dissolving in ethanol and adding 2.5 N sodium hydroxide until the product, 9-fluoro-6,7-dihydro-5H- dibenzo[c,e]azepin-5-one, precipitates, mp. 205-206C.

When 6-acetyl, benzoyl, methyl or allyl-9-amino-6,7- dihydro-SH-dibenzo[c,elazepin-S-one is substituted for 9-amino-6,7-dihydro-5H-dibenzo[c,e]azepin- 5-one, there is obtained 6-acetyl, benzoyl, methyl or allyl-9-fluoro-6,7-dihydro-5H-dibenzo[c,e]azepin- 5-one.

EXAMPLE 4 To 2 g. of 9-fluoro-6,7-dihydro-5H-dibenzo[c,e]azepin-S-one is added 20 ml. of acetic anhydride. The resulting mixture is heated on the steam-bath at 9095C. overnight. The excess solvent is removed in vacuo and the residue crystallizes upon addition of ether. The crude product, 6-acetyl-9-fluoro-6,7-dihydro-5H- dibenzo- [c,e]azepin-S-one is crystallized from benzene.

EXAMPLE 5 9-Cyano-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one A mixture which contains 5 g. (.022 mole) of 9- bromo-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one and 4.5 g. of cuprous cyanide is stirred and refluxed in 150 ml. of dry dimethylformamide. After 20 hours, the reaction mixture is concentrated to about half the original volume, cooled and added to ml. of ferric chloride solution (4 parts ferric chloride, 1 part concentrated hydrochloric acid and 6 parts water). The reaction is then stirred for 30 minutes and diluted with 100 ml. of water. The mixture is extracted with 3 X 250 ml. of ethyl acetate. The compound extracts are washed with water and then with aqueous sodium bicarbonate. The ethyl acetate is evaporated and the residue is purified by crystallization from dimethylformamide-ether to obtain the product, 9-cyano-6,7-dihydro- 5H-dibenzo[c,e]azepin-5-one, mp. 272-274C.

' 25 When 6-methyl or allyl-9-fluoro-6,7-dihydro-5H- dibenzo[c,e]azepin--one is substituted for 9-bromo- 6,7-dihydro-5H-dibenzo[c,elazepin-S-one, there is obtained 6-methyl or allyl-9-cyano-6,7-dihydro-5H- dibenzo[c,e]azepin-S-one.

EXAMPLE6 9-Carbamyl-6,7-dihydro-5 H-dibenzo[c,e ]azepin-5-one Six hundred Mg. (.002 mole) of 9-cyano-6,7- dihydro-SH-dibenzo[c,e]azepin-5-one is dissolved in ml. of concentrated sulfuric acid and allowed to stand at room temperature overnight. The solution is then poured onto ice and the crude product, 9- carbamyl-6,7-dihydro-5H-dibenzo[c,e]azepin-S-one, is filtered. The crude product is recrystallized from dimethylformamide-water, mp. 298C. 4

When 6-acetyl, benzoyl, methyl or allyl-9-cyano-6,7- dihyro-5H-dibenzo[c,e]azepin-5-one is substitutedfor 9-cyano-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one, there is obtained 6-acetyl, benzoyl, methyl or a1lyl-9- carbamoyl-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one.

EXAMPLE 7 EXAMPLE 8 9-( N ,N-Dimethylcarbamyl )-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one One gram (.004 mole) of 9-carboxy-6,7-dihydro-5H- dibenzo[c,e]azepin-S-one is refluxed in ml. of thionyl chloride for 3 hours. The excess reactant is removed in vacuo and the residue is dissolved in acetone. The resulting solution is added to a cooled and stirred solution of 20 ml. of 40% aqueous dimethylamine over a 15 minute period. The crude product, 9-(N,N- dimethylcarbamoyl)-6,7-dihydro-5H-dibenzo[c,elazepin-S-one, is filtered and recrystallized from dimethylformamide-ether.

When 6-methyl or allyl-9-carboXy-6,7-dihydro-5l-l- The excess solvent is removed in vacuo and'the residue crystallizes upon the addition of ether. The crude product, 6-acetyl-6,7-dihydro-5H-dibenzo[c,e]azepin- 5-one, is recrystallized from benzene, m.p. l23l24C.

When benzoic anhydride or phenylpropionyl chloride is substituted for acetic anhydride, there is obtained 6-benzoyl-6,7-dihydro-5H-dibenzolc,e]azepin-5-one or o-phenylpropionyl-6,7-dihydro-5H-dibenzo[c- ,e]azepin-5-one, respectively.

EXAMPLE l0 9-Nitro-6-acetyl-6,7-dihydro-5H-dibenzo[c,e]azepin- 5-one The procedure of Example 9 is repeated, except that the starting material is 9-nitro-6,7-dihydro-dibenzo[c- ,e]azepin-5-one. Using the same reaction conditions and techniques, there is obtained the product, '9-nitro- 6-acetyl-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one.

EXAMPLE ll 9-(N,N-Dimethylcarbamyl)-6-acetyl-6,7-dihydro-5l-ldibenzo[c,e]azepin-S-one The procedure of Example 9 is repeated, except that the starting material is 9-(N,N-dimethylcarbamyl)-6,7-

dihydro-5H-dibenzo[c,e]azepin-5-one. Using the same I reaction conditions and techniques, there is obtained the product, 9-(N,N-dimethylcarbamyl) 6-acetyl-6,7- dihydro-5H-dibenzo[c,e]azepin-5-one.

EXAMPLE l2 7-Succinimido-6,7-dihydro 5H-dibenzo[c,elazepin- S-one A mixture containing 2 g. of 6,7-dihydro-5H-dibenzo[c,e]azepin5-one, 2.7 g. of N-bromosuccinimide and 50 mg. of benzoyl-peroxide is refluxed in 100 ml.

dibenzo[c,e]azepin-S-one is substituted for'9-carboxy- 6,7-dihydro-5H-dibenzo[c,e ]azepin-5-one, tthere is obtained 6-methyl or allyl-9-(N,N'- dimethylcarbamoyl )-6,7-dihydro-5H-dibenzo- [c,e]azepin-5-one.

EXAMPLE 9 6-Acetyl-6,7-dihydro-5H-dibenzo[c,clazepin-S-one To 2 g. of 6,7-dihydro-5H-dibenzo[c,elazepin-S-one is added 20 ml. of acetic anhydride. The resulting mixture is heated on the steam-bath at 9095C. overnight.

of chloroform for 15 hours. The reaction solution is evaporated to a thick gum which is then dissolved in 30 ml. of ethanol. The careful addition of water causes the product to crystallize. The product, 7-succinimido-6,7- dihydro-SH-dibenzo[c,e]azepin-5-one, is purified by recrystallization with dimethylformamide-ether, mp. 281-283C.

When N-bromo-acetamide or N-bromo-phthalimide is substituted for N-bromosuccinimide, there is obtained 7-acetylimido-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one or 7-phthalimido-6,7-dihydro-5H-dibenzo[c- ,e]azepin-5-one, respectively.

EXAMPLE 13 The procedure of Example 2 is repeated, except that the starting material is 6-acetyl, benzoyl, methyl or allyl-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one. Using the same reaction conditions and techniques, there is obtained the product, 6-acetyl, benzoyl, methyl or allyl-9- nitro-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one.

EXAMPLE 14 6-Methyl-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one To a solution of 2.1 g. of 6,7-dihydro-5H-dibenzo[c- ,e]azepin-5-one in 50 ml. of cold dimethylformamide is added 240 mg. of sodium hydride with stirring. To this reaction mixture is added 1.5 g. of methyl iodide. The solution is allowed to stir at room temperature for several hours. The addition of water precipitates the product, 6-methyl-6,7-dihydro-5H-dibenzo[c,e]azepin- S-one. The product is purified by chromatography.

EXAMPLE 15 9-Nitro-6-methyl-6,7-dihydro-5H-dibenzo[c,e]azepin- -one The procedure of Example 14 is repeated, except that the starting material is 9-nitro-6,7-dihydro-5H- dibenzo[c,elazepin-S-one. Using the same reaction conditions and techniques, there is obtained the product, 9-nitro-6-methyl-6,7-dihydro-5H-dibenzo[c.e]azepin-S-one.

EXAMPLE l6 o-Acetyl-9-acetylamino-fiJ-dihydro-SH-dibenzo[c- .e lazepin-S-one 1.1 Grams (.005 mole) of 9-amino-6,7-dihydro-5H- dibenzo[c,e]azepin-5-one is heated in 20 ml. of acetic anhydride on the steam-bath at 9095C. for 18 hours. Most of the excess anhydride is removed in vacuo and the residue is tritrated with water until solidification. The product, 6-acetyl-9-acetylamino-6,7-dihydro-5H- dibenzo[c,e]azepin-5-one, is purified by crystallization from benzene.

When benzoic anhydride or propionic anhydride is substituted for acetic anhydride, there is obtained 6- benzoyl-9-benzoylamino-6,7-dihydro-5H-dibenzo[c- ,e]azepin-5-one or 6-propionyl-9-propionylamino-6,7- dihydro-S H-dibenzo[c,e]azepin-5-one, respectively.

EXAMPLE 17 9-Methylthio-6,7 dihydro-5H-dibenzo[c,e]azepin- 5-one' A mixture containing 380 mg. of copper powder, ml. of 2,4-lutidine and 660 mg. of dimethyl disulfide is heated at 125C. for 4 hours. The mixture is cooled and 1.5 g. of 9-bromo-6,7-dihydro-5H-dibenzo[c,e]azepin- 5-one is added. This mixture is heated at 155C. for 18 hours. The solvent is evaporated and the product, 9- methylthio-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one, is isolated from the residue by column chromatography.

When diphenyl disulfide or dibenzyl disulfide is substituted for dimethyl disulfide, there is obtained 9- phenylthio-6,7-dihydro-5H-dibenzo[c,elazepin-S-one or 9-benzylthio-6,7-dihydro-5H-dibenzo[c,e]azepin- 5-one, respectively.

EXAMPLE 1 8 9-Methylsulfinyl-6,7-dihydro-5H-dibenzo[c,e]azepin- 5-one To a cooled solution of 2.4 g. of 9-methylthio-6,7- dihydro-5H-dibenzo[c,e]azepin-5-one in 50 ml. of acetone and 50 ml. of methanol is added a solution of 2.1 g. of sodium periodate in 30 ml. of water over one hour. The reaction mixture is stirred overnight. Most of the organic solvent is evaporated and the crude product, 9-methylsulfinyl-6,7-dihydro-5H-dibenzo[c,elazepin- 5-one, can be recrystallized or purified by column chromatography.

When 9-phenylthio-6,7-dihydro-5l-l-dibenzo[c- ,elazepin-S-one or 9-benzylthio-6,7-dihydro-5H- dibenzo[c,e]azepin S-one is substituted for 9- methylthio-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one, there is obtained 9-phenylsulfinyl-6,7-dihydro-5H- dibenzo[c,e]azepin-5-one or 9-benzylsulfinyl-6,7- dihydro-5H-dibenzo[c,e]azepin-5-one, respectively.

EXAMPLE l9 9-Methylsulfonyl 6,7-dihydro-5H-dibenzo[c,e]azepin- 5-one To a solution containing 2.5 g. of 9-methylsulfinyl- 6,7-dihydro-5H-dibenzo[c,e]azepin-5-one and 50 ml. of acetic acid at about 20C. is added, with stirring, an excess of 30% hydrogen peroxide in acetic acid, dropwise, over 30 minutes. The reaction mixture is maintained at room temperature with slight agitation for 1.6 hours, then poured into ice and filtered to obtain the product, 9-methylsulfony1-6,7-dihydro-5H-dibenzo[c- ,elazepin-S-one.

When 9-phenylsulfinyl-6,7-dihydro-5H-dibenzolc- .elazepin-S-one or 9-benzylsulfinyl-6,7-dihydro-5H- dibenzo[c,e]a2epin-5-one is substituted for 9- methylsu1finyl-6,7-dihydro-5H-dibenzo[c,e]azepin- 5-one, there is obtained 9-phenylsulfonyl-6,7-dihydro- 5H-dibenzo[c,e]azepin-5-one or 9-benzylsulfonyl-6,7- dihydro-5H-dibenzo[c,e]azepin-5-one, respectively.

EXAMPLE 20 9-Mercapto-6.7-dihydro-5 H-dibenzo[c,e ]azepin-5-one A mixture of 1.2 g. of 9-methylthio-6,7-dihydro-5H- dibenzo[c,e]azepin-5-one and 5 g. (.04 mole of pyridine hydrochloride under a nitrogen atmosphere is placed in an oil-bath at 230C. The mixture is heated for 10 minutes, cooled and extracted with hot ethyl acetate. The ethyl acetate extracts are evaporated to obtain the product, 9-mercapto-6,7-dihydro-5H dibenzo[c,e]azepin-5-one.

EXAMPLE 21 9-Trifluoromethyl-6,7-dihydro-5H-dibenzo[c,elazepin-5-one A mixture containing 2.5 g. of 9-carboxy-6,7- dihydro-5H-dibenzo[c,e]azepin-5-one, hydrogen fluoride, and about 0.05 mole of sulfur tetrafluoride in a stainless steel lined shaker is heated at C. for 8 hours. The reaction mixture is cooled, vented, and then concentrated. The crude product, 9-trifluoromethyl- 6,7-dihydro-5H-dibenzo[c,e]azepin-5-one, can be purified by crystallization or column chromatography.

EXAMPLE 22 9-Trifluoromethyl-6-acetyl-6,7-dihydro-5H-dibenzo[c- ,e]azepin-5-one The procedure of Example 9 is repeated, except that the starting material is 9-trifluoromethyl-6,7-dihydro- 5H-dibenzo[c,e]azepin-5-one. Using the same reaction conditions and techniques, there is obtained the product, 9-trifluoromethyl-6-acetyl-6,7-dihydro-5l-l-dibenzo[c,e]azepin-5-one.

EXAMPLE 23 9-Bromo-6,7-dihydro-5H-dibenzo[c,e]azepin-S-one To a stirred solution of 2.2 g. of 9-amino-6,7- dihydro-5H-dibenzo[c,e]azepin-S-one, 25 ml. of concentrated sulfuric acid and 25 ml. of water at 0C. is added a solution which contains 1 g. of sodium nitrite in 10 ml. of water over 15 minutes. The reaction is stirred for another 30 minutes at 0C., then added in portions of a solution of 5 g. of cuprous bromide in 15 ml. of 48% hydrogen bromide which is heated on the steam-bath at ca. 60C. for 20 minutes. The reaction mixture is filtered and the crude product, 9-bromo-6,7- dihydro-5H-dibenzo[c,e]azepin-5-one, is purified by elution on alumina with ethyl acetate. The m.p. of pure material is 228230.C.

When cuprous chloride or cuprous iodide is substituted for cuprous bromide, and the corresponding halo EXAMPLE 24 9-Methoxy-6,7-dihydro-5H-dibenzo[c,elazepin-S-one 2.2 Grams of 9-hydroxy-6,7-dihydro-5H-dibenzo[c- .elazepin-S-one is dissolved in 30 ml. of dry dimethylformamide. The solution is cooled in ice and 810 mg. of sodium methoxide is added. The mixture is stirred at room temperature for 15 minutes, then cooled in ice and 2.1 g..of methyl iodide is added over 10 minutes. The reaction mixture is stirred in ice an additional minutes and then at room temperature for an hour. The reaction is warmed on the steam-bath for minutes, filtered and the filtrate is diluted with 0.5 N sodium hydroxide solution until the product crystallizes. The product, 9-methoxy-6,7-dihydro-5H-dibenzo[c,e]azepin-S-one, is purified from benzene-petroleum ether, mp. 183C.

When benzyl chloride is substituted for methyl iodide, there is obtained 9-benzyloxy-6,7-dihydro-5H- dibenzo[c,e]azepin-5-one.

EXAMPLE 25 9-Hydroxy-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one 1.1 Grams of 9-amino-6,7-dihydro-5H-dibenzo[c- .elazepin-S-one is dissolved in 40 ml. of 6 N sulfuric acid. The solution is cooled in ice while'adding, with agitation, 380 mg. (0.006 mole) of sodium nitrite in 5 ml. of water over 10 minutes. The reaction mixture is maintained in ice for 30 minutes and allowed to reach room temperature over 1 hour. The solution is warmed on the steam-bath for 25 minutes and the crude'product is filtered. The crude product, 9-hydroxy-6,7- dihydro-5H-dibenzo[c,e]azepin-5-one, is purified by dissolving in 2.5 N sodium hydroxide and precipitated by neutralizing with acetic acid, mp. 290C, dec.

EXAMPLE 26 EXAMPLE 27 9-Amidino-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one Into a cold suspension of equal molar quantities of 9-cyano-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one and ethanol is passed dry hydrogen chloride until the mixture is saturated. After standing 24 hours, the excess hydrogen chloride is removed and an excess of aqueous ammonia added. The resulting compound is 9-amidino-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one.

EXAMPLE 28 9-Ureido-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one 9-Amino-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one is dissolved in acetic acid and treated with a slight excess of potassium isocyanate. The resulting product is 9-ureido-6,7-dihydro-5H-dibenzo[c,elazepin-S-one.

EXAMPLE 29 9-( Ethylcarbamyloxy )-6-methyl-6,7-dihydro-5 H- dibenzo[c,e lazepin-S-one To a mixture of 9-hydroxy-6-methyl-6,7-dihydro-5H- A dibenzo[c,e]azepin-5-one in dioxane is added ethyl isocyanate to yield the title compound.

EXAMPLE 30 9-Sulfamyl-6-methyl-6,7-dihydro-5H-dibenzo[c,elazepin-5-one 6-Methyl-6,7-dihydro-5H-dibenzo[c,elazepin-S-one is added with stirring to a cold excess of chlorosulfonic acid. After the addition is complete, the solution is slowly allowed to rise to room temperature. After 2 hours, the solution is cautiously added to cold concentrated ammonium hydroxide. The title compound precipitates.

EXAMPLE 31 9-( l ,1,2-Trifluoro-2-chloroethoxy)-6,7-dihydro-5H- dibenzo[c,e]azepin-5-one Into a solution of 5 grams of 9-hydroxy-6,7-dihydro- SH-dibenzo[c,e]azepin-5-one in 150 ml. of dimethylformamide is added 500 mg. of sodium methoxide and an excess of trifluorochloro ethylene. This solution is heated in a bomb at C. for 6 hours. The addition of water precipitates the product.

EXAMPLE 32 EXAMPLE 33 9-Carbamyl-6,7-dihydro-5 H-dibenzo[c,e]azepin-5-one The above compound (9-carbethoxy-6,7-dihydro- 5H-dibenzo[c,e]azepin-5-one) is warmed in ammonium hydroxide for one hour to give the title compound.

EXAMPLE 34 6-(Methylthiomethyl)-6,7-dihydro-5H-dibenzo[c- ,e]azepin-5-one A cold solution of 6,7-dihydro-5H-dibenzo[c,elazepin-S-one in dimethylformamide is treated with one equivalent of sodium hydride. After the reaction is over, an equivalent of chloromethyl methylsulfide is added. The reaction mixture is stirred for 2 hours, and then water is added to precipitate the product.

EXAMPLE 35 6-Methylsulfinylmethyl-6,7-dihydro-5 H-dibenzo[c- ,elazepin-S-one EXAMPLE 36 6-Acetyl-9-acetylaminol -nitro-6,7-dihydro-5H- dibenzo[c,e]azepin-S-one 1.5 Grams (0.005 mole) of 6-acetyl-9-acetylamino- 6,7-dihydro-H-dibenzo[c,e]azepin-5-one in 5 ml. of sulfuric acid is treated with 20 ml. of concentrated sulfuric acid which contains 0.5 g. (0.005 mole) of potassium nitrate. The resulting mixture is maintained with stirring at 0C. to C. for 6 hours and then poured onto ice to precipitate the product.

EXAMPLE 37 9-Methoxy-lO-nitro-6,7-dihydro-5H-dibenzo[c,e]azepin-S-one A solution of 2.4 g. (0.01 mole) of 9-methoxy-6,7- dihydro-S H -dibenzo[c,elazepin-S-one in 30 ml. of concentrated sulfuric acid is tritrated with a solution containing 1 g. (0.0] mole) of potassium nitrate in 10 ml. of concentrated sulfuric acid at ice temperature. After 5 hours at ice temperature the solution is poured onto ice and the product precipitates.

Other representative compounds in addition to those previously indicated which may be prepared according to the above processes include:

9-dimethylamino-6,7-dihydro-5H-dibenzo[c,e]azepin-S-one 6-methyl-9-dimethylamino-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one 3,9-dimethylthio-6-aminomethyl-6,7-dihydro-5H- dibenzo[c,e]azepin-S-one 6-carboxymethyl-9-methylamino-6,7-dihydro-5H- dibenzo[c,e]azepin-S-one 6-vinyl-9-nitro-6,7-dihydro-5H-dibenzo[c,e]azepin- 5-one 7-phthalimido-6,7-dihydro-5H-dibenzo[c,e]azepin- 5-one 7-acetylimido-6-methoxymethyl-6,7-dihydro-5H- dibenzo[c,e]azepin-S-one 9-methylsulfinyl-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one I 9-methylsulfonyl-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one 9-dimethy1carbamoyl-6,7-dihydro-5H-dibenzo[c- ,elazepin-S-one 9-phenoxy-6.7-dihydro-5H-dibenzo[c,elazepin- ,5-one 9-phenethyloxy-6,7-dihydro-5 H-dibenzo[c.e]azepin- 5-one 9-carboxymethyl-6.7dihydro-5H-dibenzo[c,e]azepin-S-one 9-a (carboxy)ethyl-6,7-dihydro-5H-dibenzo[c- ,e]azepin-5-one 9-a-(carboxy)ethenyl-6,7-dihydro-5H-dibenzo[c- ,e]azepin-5-one 9-a-(carboxy)propyl-6,7-dihydro-5H-dibenzo[c- ,e]azepin-5-one 3,9-dipropenylcarbamoyl-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one 9-benzylsulfonyl-6,7-dihydro-5H-dibenzo[c.e]azepin-5-one 9-phenylsulfinyl-6,7-dihydro-5H-dibenzo[c,elazepin-5-one 9-benzylthio-6,7-dihydro-5H-dibenzo[c.e]azepin- 5-one 9-p-chlorobenzoyl-6-acetyl-6,7-dihydro-5 H-dibenzo[c,e]azepin-5-one 3,9-dinitro-7-succinimido-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one 3,9-diamino-6-methoxymethyl-6,7-dihydro 5H- dibenzo[c,e]azepin-S-one 9-acetylamino-6-carboxymethyl-6,7 dihydro5H- dibenzolc,e]azepin-5-one 3.9-dihydroxy-6-acetyl-6,7-dihydro-5H-dibenzolc- ,elazepin-S-onc 9-mercapto-6-ethyl-6,7-dihydro-5H-dibenzo[c- ,elazepin-S-one 3,9-bis-methylethylamino-6.7-dihydro-5H-dibenzo[c,e]azepin-5-one 9-anilino-6,7-dihydro-5H-dibenzo[c,elazepin-S-one 3,9-diacetylamino--acetyl-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one 9-p-tolylthio-6,7-dihydro-5H-dibenzo[c,e]azepin- 5-one 9-phenylsulfonyl 6-vinyl-6,7-dihydro-5H-dibenzo[c- ,e]azepin-5-one 3,9-diphenylsulfonyl-6-vinyl-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one 9-cyano-6-methyl-6,7-dihydro-5H-dibenzo[c,elazepin-5-one 3,9-dibromo-6-carboxymethyl-6,7-dihydro-5H- dibenzo[c,e]azepin-S-one 3,9-dicyano-6,7-dihydro-5H-dibenzo[c,elazepin- 5-one 9-carboxy-6-hydroxymethyl-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one 3,9-dicarbamoyl-6-propenyl-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one 9-nitro-6-ethyl-7-acetylimido-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one 3,9-dimethylthio-6-benZoyl-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one 3,9-diphenylsulfinyl-6-benzoyl-6,7-dihydro-5H- dibenzo[c,e]azepin-S-one 9-fluoro-6-acetyl-6,7-dihydro-5H-dibenzo[c,e]azepin-S-one '9-(p-methylthiobenzylamino)-6,7-dihydro-5H- dibenzo[c,e]azepin-S-one What is claimed is:

l. A compound of the formula:

U R! 12L R4 wherein R is hydrogen R is hydrogen or nitro;

R, is hydrogen, alkyl of up to three carbon atoms, al-

kanoyl of up to four carbon atoms, benzoyl, carbalkoxy of up to four carbon atoms, alkenyl of up to four carbon atoms, alkylthioalkyl of up to four carbon atoms, or methylsulfinylmethyl;

R, isv hydrogen, succinimido, acetylimido or phthalimido;

R is hydrogen, nitro, amino, halo. alkoxy of up to four carbon atoms, hydroxy, cyano, carbamyl, carboxy, dialkylcarbamyl of up to four carbon atoms, alkanoylamino of up to four carbon atoms, benzoylamino, alkylthio of up to four carbon atoms, phcnylthio, benzylthio, alkylsulfinyl of up to three carbon atoms, alkylsulfonyl of up to three carbon atoms, phenysulfinyl, benzylsulfinyl, mercapto, trifluoromethyl, amidino, ureido, alkylcarbamyloxy of up to four carbon atoms or sulfamyl; and R is hydrogen;

with the proviso that when R, is hydrogen or methyl at least one of R R, or R is other then hydrogen.

2. A compound of the formula:

R is hydrogen, nitro, amino, fluro, bromo, chloro,

dimethylcarbamyl, acetylamino, benzoylamino, allyl propionylamino, methylthio, phenylthio, benzylthio, methylsulfinyl, methylsulfonyl, phenylsulfinyl, benzylsulfinyl, mercapto, trifluoromethyl, amidino, ureido, ethylcarbamyloxy, or sulfamyl; and

R is hydrogen;

with the proviso that when R, is hydrogen, or methyl at least one of R R or R is other than hydrogen.

3. A compound of the formula:

' Rn Rio wherein R, R, R, and R,,, are each hydrogen;

R is alkanoyl of up tofour carbon atoms; and

R,, is hydrogen, nitro, amino, halo, alkoxy of up to four carbon atoms, hydroxy, cyano, carbamyl, carboxy, dialkylcarbamyl of up to four carbon atoms, alkanoylamino of up to four carbon atoms, benzoylamino, alkylthio of up to four carbon atoms, phenylthio, benzylthio, alkylsulfinyl of up to three carbon atoms, alkylsulfonyl of up to three carbon atoms, phenysulfinyl, benzylsulfinyl, mercapto, trifluoromethyl, amidino, ureido, alkylcarbamyloxy of up to four carbon atoms or sulfamyl.

4. A compound of claim 3 wherein R, is acetyl.

5. A compound of claim 3 wherein R1, is butyryl.

6. A compound of claim 3 wherein R is hydrogen R is acetyl.

7. A compound of claim 3 wherein 5 R,, is hydrogen, and

R is butyryl. 8. A compound of the formula:

R R10 l0 R =0 i N wherein Y R, R; R, and R,,, are each hydrogen, R is alkenyl of up to four carbon atoms, and

R,, is hydrogen, nitro, amino, halo, alkoxy of up to four carbon atoms, hydroxy, cyano, carbamyl, carboxy, dialkylcarbamyl of up to four carbon atoms, alkanoylamino of up to four carbon atoms, phenylthio, benzylthio, alkylsulfinyl of up to three carbon atoms, alkylsulfonyl of up to three carbon atoms, phenysulfinyl, benzylsulfinyl, mercapto, trifluoromethyl, amidino, ureido, alkylcarbamyloxy ofup to four carbon atoms or sulfamyl. 9. A compound of claim 8 wherein R is allyl.

10. A compound of the formula:

i Rn R10 ri k I R 4 l wherein R R, R, and R,,, are each hydrogen, R, is amino, and R is hydrogen, nitro, amino, halo, alkoxy of up to four carbon atoms, hydroxy, cyano, carbamyl, carboxy, dialkylcarbamyl of up to four carbon atoms,

alkanoylamino of up to four carbon atoms, phenylthio, benzylthio, alkylsulfinyl of up to three carbon atoms, alkylsulfonyl of up to three carbon atoms, phenysulfinyl, benzylsulfinyl, mercapto, trifluoromethyl, amidino, ureido, alkylcarbamyloxy of up to four carbon atoms or sulfamyl. 11. A compound of the formula:

R9 Rm R1 R2 i f wherein R; R, R, and R,,, are each hydrogen, R, is halogen, and R is hydrogen, nitro, amino, halo, alkoxy of up to four carbon atoms, hydroxy, cyano, carbamyl, car- 12. A compound of claim 11 wherein R, is fluoro and R is hydrogen. 13. A compound of claim 11 wherein R is chloro and R is hydrogen. 

2. A compound of the formula:
 3. A compound of the formula:
 4. A compound of claim 3 wherein R3 is acetyl.
 5. A compound of claim 3 wherein R3 is butyryl.
 6. A compound of claim 3 wherein R9 is hydrogen R3 is acetyl.
 7. A compound of claim 3 wherein R9 is hydrogen, and R3 is butyryl.
 8. A compound of the formula:
 9. A compound of claim 8 wherein ''R3 is allyl.
 10. A compound of the formula:
 11. A compound of the formula:
 12. A compound of claim 11 wherein R1 is fluoro and R9 is hydrogen.
 13. A compound of claim 11 wherein R1 is chloro and R9 is hydrogen. 